WO2020122670A1 - Composition pharmaceutique, comprenant du tolvaptan, pour la préparation d'une dispersion solide et son procédé de préparation - Google Patents

Composition pharmaceutique, comprenant du tolvaptan, pour la préparation d'une dispersion solide et son procédé de préparation Download PDF

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WO2020122670A1
WO2020122670A1 PCT/KR2019/017709 KR2019017709W WO2020122670A1 WO 2020122670 A1 WO2020122670 A1 WO 2020122670A1 KR 2019017709 W KR2019017709 W KR 2019017709W WO 2020122670 A1 WO2020122670 A1 WO 2020122670A1
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tolvaptan
solid dispersion
preparing
pharmaceutical composition
pharmaceutically acceptable
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PCT/KR2019/017709
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English (en)
Korean (ko)
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구본암
전세화
권세욱
신용훈
서정훈
이정욱
정승준
윤대호
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명인제약주식회사
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the present invention relates to a pharmaceutical composition for preparing a solid dispersion containing tolvaptan and a method for manufacturing the same. Specifically, tolvaptan (7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H- as active ingredient Benzoazepine), a water permeation enhancer, and an organic solvent, to a pharmaceutical composition for preparing a solid dispersion.
  • Tolvaptan is a compound of the formula (I): 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tete Rohydro-1H-benzoazepine, used as a vasopressin antagonist.
  • Drugs using tolvaptan as an active ingredient are commercially available as Samsuka tablets, and are clinically significant hypervolemic or euvolemic in patients with heart failure and antidiuretic hormone secretion syndrome (SIADH).
  • the treatment of sodiumemia, or the first administration corresponds to stages 1 to 3 of chronic renal disease, and the rapid progression of autosomal dominant polycystic kidney disease (ADPKD) delays the formation of cysts and delayed renal function in adult patients.
  • ADPKD autosomal dominant polycystic kidney disease
  • Tolvaptan is very poorly soluble in water, and when preparing a solid preparation using conventional formulation technology, it has a problem of low solubility and low absorption into the digestive tract, resulting in low bioavailability.
  • the solubility in water is 10-1600 times greater than that in the amorphous form, bioavailability may be significantly increased when converted to the amorphous form.
  • the amorphous form has a problem that storage stability is low because it tends to be recrystallized into a crystalline form with low free energy over time.
  • Attempts to increase the surface area by miniaturizing the particle size may be effective in improving the dissolution rate of a material having a small dissolution rate, but there is a limit that does not change the intrinsic solubility of the material, and there is a hammer mill or jet mill. ), it is refined by using a grinder such as ), and thus is limited in application depending on the energy reactivity of the compound.
  • Methods for improving solubility by making a microemulsion using a solubilizing agent such as a surfactant are frequently used, but use is limited due to toxicity of a solubilizing agent, an organic solvent, and a surfactant.
  • a solid dispersion is a system in which drug particles are dispersed in a solid, water-soluble polymer matrix, which can increase the surface area of the drug particles by reducing the size of the drug particles.
  • the drug is converted to amorphous, partially Or, since it exists in an amorphous state as a whole, it is efficient in terms of increasing the solubility of the drug and storage.
  • a spray drying method and a melt extrusion method are known as a method for producing a solid dispersion.
  • the melt extrusion method is a method of forming a solid dispersion by melting a drug and a water-soluble polymer mixture above the melting point of the drug and the glass transition temperature of the polymer mixture, thereby converting the drug into an amorphous state and imparting plasticity to the polymer to extrude it.
  • a water-soluble polymer mixture above the melting point of the drug and the glass transition temperature of the polymer mixture
  • the spray drying method is a method of preparing a solid dispersion by mixing in a suitable solvent according to the properties of a drug and a water-soluble polymer, and there is a problem that it is difficult to find a solvent that can dissolve a poorly water-soluble drug and a water-soluble polymer together.
  • Japanese Patent Laid-Open No. 1999-21241 discloses a method of powdering by dissolving tolvaptan and hydroxypropyl cellulose in an organic solvent and evaporating and removing the organic solvent.
  • Japanese Patent Laid-Open No. 1999-21241 discloses a method of powdering by dissolving tolvaptan and hydroxypropyl cellulose in an organic solvent and evaporating and removing the organic solvent.
  • due to the residual and low disintegration properties of the organic solvent Therefore, there are still problems to be solved.
  • the present inventors have repeatedly studied to improve the disintegration, solubility, and absorbability of tolvaptan, by adding a moisture permeation enhancer and finding an organic solvent capable of effectively dissolving them. By manufacturing, the present invention was completed.
  • An object of the present invention is to provide a pharmaceutical preparation for improving bioavailability by improving the disintegration, solubility and absorbability of tolvaptan.
  • the present invention is to provide a pharmaceutical composition for the preparation of a solid dispersion and a method for manufacturing the same, comprising tolvaptan, a water permeation enhancer and an organic solvent.
  • the present invention provides a pharmaceutical composition for preparing a solid dispersion, comprising tolvaptan or a pharmaceutically acceptable salt thereof, a water permeation enhancer and an organic solvent.
  • the moisture penetration enhancer may be polyvinylpyrrolidone.
  • the weight ratio of polyvinylpyrrolidone to the tolvaptan or a pharmaceutically acceptable salt thereof may be 0.5 or more, preferably 0.5 or more and 1 or less, and more preferably 0.5.
  • the organic solvent may include one or more from the group consisting of methylene chloride and ethanol.
  • the organic solvent is preferably used in a minimum amount to dissolve the tolvaptan and the moisture permeation enhancer in order to secure the safety and economic efficiency of the process in the manufacture of the solid dispersion.
  • the weight ratio of the tolvaptan or the pharmaceutically acceptable salt thereof to the organic solvent may be 11 or more, preferably 11 or more and 20 or less, and more preferably 11 or more and 13 or less.
  • the weight ratio of the methylene chloride to the tolvaptan or a pharmaceutically acceptable salt thereof may be 9 or more and 16 or less, and preferably 9 or more and 11 or less.
  • the solid dispersion may be that the solubility of tolvaptan in water may be increased by 10 times or more, preferably 20 times or more, more preferably 22 times or more, compared to the tolvaptan raw material powder.
  • the present invention comprises a solid dispersion prepared using the pharmaceutical composition and at least one additive selected from the group consisting of lactose hydrate, starch, microcrystalline cellulose, low-substituted hydroxypropylcellulose and hydroxypropylmethylcellulose It provides a pharmaceutical formulation characterized in that.
  • the present invention also provides a method for preparing solid dispersion by dissolving tolvaptan or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone in an organic solvent.
  • the organic solvent may include one or more from the group consisting of methylene chloride and ethanol.
  • the weight ratio of polyvinylpyrrolidone to the tolvaptan or a pharmaceutically acceptable salt thereof may be 0.5 or more, preferably 0.5 or more and 1 or less, and more preferably 0.5.
  • the weight ratio of the organic solvent to the tolvaptan or a pharmaceutically acceptable salt thereof may be 11 or more, preferably 11 or more and 20 or less, and more preferably 11 or more and 13 or less.
  • the weight ratio of the methylene chloride to the tolvaptan or a pharmaceutically acceptable salt thereof may be 9 or more and 16 or less, preferably 9 or more and 11 or less.
  • the present invention provides a method for preparing a pharmaceutical formulation comprising the following steps:
  • the pharmaceutical preparation may be a tablet for oral administration.
  • the solid dispersion prepared according to the present invention has an effect of significantly increasing the dissolution rate of tolvaptan compared to tolvaptan raw material powder. Therefore, the pharmaceutical preparation prepared using the solid dispersion of the present invention has the effect of increasing the absorbability of the poorly soluble drug tolvaptan and improving the bioavailability.
  • 1 to 4 is a graph showing the dissolution rate according to the pH conditions of the pharmaceutical formulation and the control drug (Samsuka tablet) according to the present invention.
  • the present invention is tolvaptan (7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine ) Or a pharmaceutically acceptable salt thereof, a water permeation enhancer, and an organic solvent.
  • the "pharmaceutically acceptable salt” of the present invention is an organic acid selected from the group consisting of oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid, or an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid. It may be in the form of acid addition salt formed by, but is not limited thereto.
  • the "moisture penetration enhancer" of the present invention is a component used to accelerate the elution of the active ingredient from the tablet by absorbing moisture, sodium croscarmellose, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, cross Povidone, polyvinylpyrrolidone, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene glycol, collidone CL, alginic acid, sodium alginate, carboxymethylcellulose calcium salt and sodium salt , Colloidal silicon dioxide, guar gum, magnesium aluminum silicate, powdered cellulose and starch may be selected from one or more, but is not limited thereto.
  • the "organic solvent” of the present invention is one or more selected from the group consisting of alcohols, ketones, methylene chloride, dichloromethane, dichloroethane, chloroform and 2-methyl 2-butene. And may not be limited thereto.
  • the alcohols may be methanol, ethanol, isopropanol, 1-butanol, 2-butanol, isobutyl alcohol, isopentyl alcohol or isopropyl alcohol, and ketones are acetone, methyl ethyl ketone (MEK), methylbutyl ketone (MBK) Or methyl isobutyl ketone (MIBK).
  • the present invention comprises a solid dispersion prepared using the pharmaceutical composition and at least one additive selected from the group consisting of lactose hydrate, starch, microcrystalline cellulose, low-substituted hydroxypropylcellulose and hydroxypropylmethylcellulose It relates to a pharmaceutical formulation.
  • Starch includes, but is not limited to, corn starch, wheat starch, potato starch, and the like.
  • the content of the hydroxypropoxyl group in low-substituted hydroxypropyl cellulose is generally in the range of 5.0 to 16.0% by weight, but is not limited thereto.
  • Hydroxypropylmethylcellulose hydroxypropylmethylcellulose or hypromellose, "HPMC” is a type of cellulose derivative having a methoxy group (-OCH 3 ), hydroxypropoxy group (-OCH 2 CH(CH 3 )OH) or hydrogen as a substituent.
  • compositions and formulations containing tolvaptan of the present invention have the effect of treating hyponatremia or delaying the progression of cyst formation and renal function decline in autosomal dominant polycystic kidney disease (ADPKD).
  • ADPKD autosomal dominant polycystic kidney disease
  • the pharmaceutical formulation of the present invention may further include suitable carriers, excipients, and diluents commonly used.
  • Carriers, excipients, and diluents that may be included in the formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto.
  • Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Tolvaptan (g) 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 Polyvinylpyrrolidone (K-30, g) 50 50 50 50 50 50 50 50 50 50 50 50 50 50 Methylene chloride (g) 1670 1390 1250 1110 1040 975 920 835 765 700 Ethanol (g) 420 350 320 280 260 245 220 210 195 180
  • Example 7 the solubility was measured for the solid dispersion of Example 7 in which all tolvaptan was dissolved using the smallest amount of organic solvent. After dissolving the raw material of tolvaptan or the solid dispersion of tolvaptan in Example 7 in purified water at the concentrations shown in Table 2 below, each detection amount was analyzed and compared using HPLC.
  • Detection amount (Area) Solubility ratio (tolvaptan solid dispersion/tolvaptan) Tolvaptan Example 7 Tolvaptan concentration (mg/mL) 0.003 3439.5 52729.5 15.33 0.005 3723.3 97028.3 26.06 0.01 6293.3 154429.8 24.54 0.02 9573.8 312601.5 32.65
  • Example 7 As shown in Table 2 above, it was confirmed that the solid dispersion of Example 7 exhibited a remarkable increase in solubility of 15 times or more compared to tolvaptan raw material powder.
  • Example 7 the solid dispersion of Example 7 using polyvinylpyrrolidone as the moisture permeation enhancer is more solid than that of the comparative example using hydroxypropylcellulose, hydroxypropylmethylcellulose or polyethylene glycol as the moisture permeation enhancer. It was found that the solubility of tolvaptan increased significantly.
  • Example 7 In order to compare the solubility of the tolvaptan solid dispersion according to the content of polyvinylpyrrolidone as a moisture permeation enhancer, in the same manner as in Example 7, the solid dispersions containing different contents of polyvinylpyrrolidone were used. It was prepared (Examples 11 to 16).
  • the solid dispersion was measured in the same manner as in Experimental Example 1 to measure the increase in solubility in the raw powder of tolvaptan and is shown in Table 4 below.
  • Example 11 Example 12
  • Example 13 Example 7
  • Example 14 Example 15
  • Example 16 Methylene chloride (g) 920 Ethanol (g) 220 Tolvaptan (g) 100 Polyvinylpyrrolidone (k-30, g) 10 20 40 50 100 200 500 Tolvaptan: polyvinylpyrrolidone (weight) 1: 0.1 1: 0.2 1: 0.4 1: 0.5 1: 1 1: 2 1: 5 Solubility ratio (tolvaptan solid dispersion / tolvaptan) 4.8 13.5 21.6 23.3 24.1 22.9 23.5
  • Granules were prepared using a mixture of a solid dispersion of Example 7, corn starch, lactose hydrate, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and a binding solution in which hydroxypropyl methyl cellulose was dissolved in purified water. After mixing the granules of Blue No. 2 with aluminum granules, lubricating with magnesium stearate, and tableting with the same tableting hardness as the control drug (samsuka tablets 15 mg, Otsuka Pharmaceutical Co., Ltd.) to obtain tablets having the composition and content of Table 5 below. It was prepared (Example 17).
  • Example 17 ingredient Content (mg) Tolvaptan 15.00 Lactose hydrate 102.32 Corn starch 20.00 Microcrystalline cellulose 20.00 Polyvinylpyrrolidone 7.50 Hydroxypropylmethylcellulose 4.00 Low-substituted hydroxypropyl cellulose 9.00 Blue No. 2 Aluminum Lake 0.18 Magnesium stearate 2.00
  • Test method Dissolution test method 2nd method (paddle method)
  • Elution medium 900 mL of purified water containing 0.22% sodium lauryl sulfate (SLS)
  • Dissolution conditions Dissolution time (minutes) 0 5 10 15 30 45 60 90 120 180 240 360 pH 1.2 Samskajeong 0 11.0 21.0 28.5 41.0 51.7 59.0 70.3 75.3 - - - Experimental Example 1 0 16.3 27.4 36.1 50.6 59.9 65.3 72.0 76.7 - - - pH 4.0 Samskajeong 0 12.4 22.3 28.5 44.8 54.5 61.3 69.2 74.1 79.2 82.8 83.7 Experimental Example 1 0 15.4 29.7 36.0 51.7 60.3 65.5 70.7 74.7 77.8 79.5 80.3 pH 6.8 Samskajeong 0 14.7 24.5 37.2 45.8 54.0 61.9 69.2 73.5 78.6 79.4 83.0 Experimental Example 1 0 18.7 30.5 43.9 52.5 60.3 65.9 72.1 72.8 77.5 79.7 81.2 DW Samskajeong 0 12.2 21.3 33.4 42.7 52.1 58.7 67.4 71.6 75.9

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Abstract

La présente invention concerne une composition pharmaceutique comprenant du tolvaptan pour préparer une dispersion solide et son procédé de préparation. De façon spécifique, la présente invention concerne une composition pharmaceutique pour la préparation d'une dispersion solide, qui comprend : du tolvaptan (7-chloro-5-hydroxy-1-[2-méthyl-4-(2-méthylbenzoylamino) benzoyl]-2,3,4,5-tétrahydro-1 H-benzoazépine) en tant que principe actif; un activateur de pénétration d'humidité; et un solvant organique.
PCT/KR2019/017709 2018-12-14 2019-12-13 Composition pharmaceutique, comprenant du tolvaptan, pour la préparation d'une dispersion solide et son procédé de préparation WO2020122670A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1121241A (ja) * 1997-07-03 1999-01-26 Otsuka Pharmaceut Co Ltd 固形製剤組成物
KR20130094281A (ko) * 2010-06-25 2013-08-23 지앙수 헨그루이 메디슨 컴퍼니 리미티드 톨밥탄 고체 분산물 및 그의 제조 방법
KR20150122728A (ko) * 2013-03-01 2015-11-02 오츠카 세이야쿠 가부시키가이샤 비정질 톨밥탄을 함유하는 경구 투여 현탁제
JP2018158893A (ja) * 2017-03-22 2018-10-11 ニプロ株式会社 トルバプタン製剤およびその製造方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1121241A (ja) * 1997-07-03 1999-01-26 Otsuka Pharmaceut Co Ltd 固形製剤組成物
KR20130094281A (ko) * 2010-06-25 2013-08-23 지앙수 헨그루이 메디슨 컴퍼니 리미티드 톨밥탄 고체 분산물 및 그의 제조 방법
KR20150122728A (ko) * 2013-03-01 2015-11-02 오츠카 세이야쿠 가부시키가이샤 비정질 톨밥탄을 함유하는 경구 투여 현탁제
JP2018158893A (ja) * 2017-03-22 2018-10-11 ニプロ株式会社 トルバプタン製剤およびその製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
K. RAMESH, B. CHANDRA SHEKAR , P. KHADGAPATHI , D. V. R. N. BHIKSHAPATHI: "Design and evaluation of tolvaptan solid dispersions using hot-melt extrusion and spray drying technique-A comparative study", DER PHARMACIA LETTRE, vol. 7, no. 1, 31 January 2015 (2015-01-31), pages 218 - 231, XP055720301, ISSN: 0975-5071 *

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